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Factor XIa Inhibitors: The Quest for the Perfect Antithrombin Agents
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Any views and opinions expressed are those of the author(s) and/or participants and do not necessarily reflect the views, policy, or position of EP Lab Digest or HMP Global, their employees, and affiliates.
EP LAB DIGEST. 2023;23(7):1,5-7.
There have been major advancements in the quest to make safer anticoagulant agents for the treatment of clots in atrial fibrillation (AF) and coronary artery disease (CAD). Direct oral anticoagulants (DOACs) have replaced vitamin K antagonists (VKAs) in many cases; DOACs have a safer bleeding profile than VKAs, as proven in multiple trials. However, there are still unacceptable levels of bleeding with DOAC use, leading to prescribing hesitancy and underuse.1 There are also issues with using DOACs with medical devices and mechanical valves. Thus, the search continues for safer anticoagulants.
Thrombosis can occur with CAD, AF, stroke, peripheral arterial disease (PAD), and venous thromboembolism (VTE). Heart disease and stroke are responsible for 25% of deaths worldwide.2 Currently, we have direct inhibitors of factor Xa (FXa) of the coagulation cascade, with rivaroxaban, apixaban, endoxaban, and betrixaban.
In addition, dabigatran, hirudins, and argatroban are direct inhibitors of thrombin. These drugs target thrombin within the common pathway and via FXa. A new suggested approach to anticoagulation is targeting factor XI (FXI) in the intrinsic pathway. To understand the difference between current therapies and the new suggested approach, one needs to review the difference between thrombosis formation and hemostasis, and the organization of the coagulation cascade.
Coagulation Cascade Review and FXI
The coagulation cascade is usually labeled and explained by discussing the 3 sections: the intrinsic or contact pathway, the extrinsic or tissue factor pathway, and the common pathway. The intrinsic or contact pathway is activated by factors in the bloodstream; endothelial injury leads to eventual thrombosis formation down in the common pathway.
The extrinsic pathway or tissue factor pathway is activated when injury occurs outside the circulation. Tissue thromboplastin is released, the common pathway in engaged, and a clot is formed. The common pathway is where both intrinsic and extrinsic pathways lead. Prothrombin leads to thrombin, fibrinogen to fibrin, and fibrin to clot.
Thrombosis is an intravascular process. Plaque triggers “pathologic blood clotting” via platelet activation and coagulation. FXI is triggered by tissue factor (TF) or via the intrinsic pathway. The end result is clot generation. Clots form in the blood vessel lumen and thrombosis compromises blood flow. Thrombosis can also be initiated by contact of blood with valves, extracorporeal circuits, or any implanted devices. An additional factor of note is that thrombin feedback to FXI causes an expansion of the thrombin effect by repeating the cycle (Figure).
The goal of hemostasis is to seal the leak and stop the bleeding, which minimizes blood loss. Hemostasis is an extravascular process; tissue factor from surrounding vessels initiates this. Vascular injury leads to TF, triggering major thrombin generation and back activation of FXI by thrombin. This latter activity is not necessarily needed for hemostasis. Production of thrombin and fibrin are the end steps in both hemostasis and thrombosis.
FXI is produced by the liver and is a part of the contact or intrinsic pathway. FXI can be activated by FXIIa or by feedback from thrombin in the common pathway. An increase in thrombin depends on activation of FXI. Therefore, FXI may actually be more important for thrombosis formation and is possibly not needed for hemostasis at all.3,4
Patients with FXI deficiency do not seem to have spontaneous bleeding and these patients have a lower stroke risk; they have little or no bleeding tendency. They will have some bleeding after trauma to certain tissues: the oropharynx and urinary tract. However, the central nervous system, gastrointestinal system, joints, and muscles are not affected. On the other hand, patients with elevated FXI levels have a higher stroke risk as well as greater risk for venous or arterial thrombosis.5-7 So, as seen in deficiency, FXI inhibition should not pose the bleeding risk of DOACs.
A major benefit of FXI inhibition might be seen in patients with implantable devices and valves. With mechanical devices, coagulation begins in the contact or intrinsic pathway with activation of FXII and generation of tissue factor (Figure). The next step is activation of FXI to FXIa. The inhibition of FXI can stop the coagulation process and avert thrombosis formation downstream.8 Dabigatran, which has been contraindicated for use with valve patients, inhibits some thrombin creation, but fails to prevent device thrombosis. Other DOACs (apixaban, rivaroxaban, etc) inhibit FXa in the common pathway where thrombin is forming, but are associated with a higher bleeding risk. So, use of an FXI inhibitor that inhibits thrombin from upstream may be safer for these patients than dabigatran and other DOACs.9
Inhibitors of FXI Currently Under Investigation
The majority of research in FXI inhibition has been evaluating 4 types of potential inhibitors, each with a slightly different mode of action (Table). None of these are on the market or approved at this time by the US Food and Drug Administration.5,9-15
The first type is the second-generation antisense oligonucleotides. These work to reduce the hepatic syntheses of FXI. Most of the research has been with fesomersen (Ionis Pharmaceuticals), which can be subcutaneously administered. Fesomersen requires a few weeks to lower FXI levels into therapeutic range, has a long half-life, and could be used once a month.
There are monoclonal antibodies that inhibit or block FXI activation, FXIa activity, or both. The most researched of these are osocimab and abelacimab. Initial work has found them to be safe and well tolerated. The mode of administration is subcutaneous (sq) or intravenous (IV), with rapid onset of action for the IV mode. Drug half-life is long; thus, monthly maintenance via subcutaneous injection would be possible.16
Aptamers are short, single-stranded oligonucleotides that bind over large surface areas on a targeted protein, in this case, targeting FXI or FXIa, inhibiting activity. Thus far, there has been only early-stage testing of aptamers. However, their administration would be IV, with rapid onset of action and a short half-life, requiring daily administration. This could be advantageous for use in the critical care setting.5,17
Lastly, there are the small molecule FXIa inhibitors. The development of this category is entering the phase 3 trial realm. The small molecule agents target FXI active sites or hepatic allosteric sites on FXIa. Asundexian and milvexian have been found to be safe and well tolerated. Milvexian has been tested in patients with normal hepatic function and mild or moderate hepatic impairment.15,18-19 Coagulation studies during treatment have shown milvexian to increase activated partial thromboplastin time (APTT) without changing prothrombin time.20 Asundexian and milvexian have been administered intravenously and orally, have rapid onset of action (maximum plasma level at 2-4 hours), and a half-life between 12 and 17 hours, making them a once- or twice-daily possibility.12,19,21
The different administration profiles seen with the drug categories could fit with varying treatment goals. For the critically ill patient or those undergoing interventional procedures, aptamers may be best due to the IV administration and rapid onset and offset of effect. A weekly administered drug may work for hemodialysis patients. Monthly administration could work with cancer-associated thromboses during a monthly oncology visit. Short half-life IV or oral administration could work with peri-interventional needs. Another benefit may be the possibility of once- or twice-a-month injections, a feature that may increase drug compliance for some patients.13
Clinical Trials
Studies have been conducted on all the categories of inhibitors, some studies on a basic laboratory level and others as phase 1 and 2 studies. These have included prevention studies, safety studies, comparison studies, and dose-finding studies. The phase 2 trials initially began with use of the agents in orthopedic surgery patients, with hip and knee surgeries. This group has historically been the starting point for testing the efficacy of anticoagulant therapies, as deep vein thrombosis of the leg can easily be detected with venography. Such study results have shown reduced thrombosis risk, decreased bleeding events, and decreased risk of VTE.22 In other studies, fesomersen, osocimab, abelacimab, and milvexian have been compared with enoxaparin. Fesomersen and osocimab have also been studied vs placebo with end-stage kidney disease and hemodialysis patients.5,9,15
The most likely agents to be used in atrial fibrillation (AF) patients at risk for stroke are the small molecule FXIa inhibitors asundexian and milvexian, which can be administered orally. Clinical trials with asundexian include the PACIFIC-AF,23 PACIFIC-STROKE,24 and PACIFIC-AMI studies.12
The PACIFIC-AF study compared asundexian to apixaban in an AF population. The reduction in bleeding was similar but slightly favored asundexian. The PACIFIC-STROKE study enrolled patients with recent non-cardioembolic ischemic stroke and compared asundexian to placebo. The subjects were kept on antiplatelet therapy in both groups. Asundexian did not reduce the stroke rate and did not increase bleeding complications. The PACIFIC-AMI study was a dose-finding safety study for prevention of myocardial infarction (MI). Recent MI patients on dual antiplatelet therapy were randomized to placebo or 10, 20, or 50 mg of asundexian. A low rate of ischemic events was reported and no significant increase in bleeding was seen.
AXIOMATIC-SSP is a phase 2 trial comparing various milvexian doses to placebo. The study objective is to prevent new ischemic stroke in patients after stroke or TIA, when milvexian is added to antiplatelet drugs (clopidogrel and aspirin).25
New phase 3 trials with asundexian are beginning to enroll patients.9 OCEANIC-AF is enrolling patients with AF and randomizing them to apixaban or asundexian with the goal of preventing stroke or systemic embolism and comparing safety. The study began in December and has an enrollment goal of 18,000 participants with a 9- to 33-month follow-up.26 The second study, called OCEANIC-STROKE, is recruiting patients with a history of stroke and randomizing them to placebo or asundexian, while keeping both groups on dual antiplatelet therapy. Data will be collected on bleeding rates and whether there is a reduction in ischemic stroke or temporary stroke-like symptoms with asundexian. This study began in January 2023 with plans to enroll 9300 participants with a 3- to 31-month follow-up.27
Reversal Agents
In the past, as new anticoagulants have been developed, there has been the need to develop or identify possible approaches for reversing their anticoagulant effect in the setting of trauma or during medical procedures where excessive bleeding is a risk. There is some work being done in this area. However, there is an established treatment regimen that has been used for patients with FXI deficiency in such situations. This involves treatment with antifibrinolytic agents and low doses of recombinant FVIIa.28 Thus, the introduction of FXI inhibitors into the clinical setting could well be safer than prior new drug introductions due to an already known reversal regimen to use in an emergency.
Future Directions
The inhibition of FXIa appears to be a promising approach for anticoagulation due to the reduced bleeding complications seen with their use. Inhibitors may be hemostasis-sparing drugs with better safety profiles. Also, we may soon be able to treat a wider range of patients with a high risk of bleeding. The beginning of these phase 3 trials brings us ever closer to the reality of seeing these agents used in the clinical setting.
Disclosure: The author has completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. She reports no conflicts of interest regarding the content herein.
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